The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.
The human immunodeficiency virus (xe2x80x9cHIVxe2x80x9d) is the causative agent for acquired immunodeficiency syndrome (xe2x80x9cAIDSxe2x80x9d)xe2x80x94a disease characterized by the destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infectionsxe2x80x94and its precursor AIDS-related complex (xe2x80x9cARCxe2x80x9d)xe2x80x94a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
As in the case of several other retroviruses, HIV encodes the production of a protease which carries out post-translational cleavage of precursor polypeptides in a process necessary for the formation of infectious virions (S. Crawford et al., xe2x80x9cA Deletion Mutation in the 5xe2x80x2 Part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolytic Processing of the gag and pol Polyproteinsxe2x80x9d, J. Virol., 53, p. 899 (1985)). These gene products include pol, which encodes the virion RNA-dependent DNA polymerase (reverse transcriptase), an endonuclease, HIV protease, and qaq, which encodes the core-proteins of the virion (H. Toh et al., xe2x80x9cClose Structural Resemblance Between Putative Polymerase of a Drosophila Transposable. Genetic Element 17.6 and pol gene product of Moloney Murine Leukemia Virusxe2x80x9d, EMBO J., 4, p. 1267 (1985); L. H. Pearl et al., xe2x80x9cA Structural Model for the Retroviral Proteasesxe2x80x9d, Nature, pp. 329-351 (1987); M. D. Power et al., xe2x80x9cNucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirusxe2x80x9d, Science, 231, p. 1567 (1986)).
A number of synthetic anti-viral agents have been designed to target various stages in the replication cycle of HIV. These agents include compounds which block viral binding to CD4+ T-lymphocytes (for example, soluble CD4), and compounds which interfere with viral replication by inhibiting viral reverse transcriptase (for example, didanosine and zidovudine (AZT)) and inhibit integration of viral DNA into cellular DNA (M. S. Hirsh and R. T. D""Aqulia, xe2x80x9cTherapy for Human Immunodeficiency Virus Infectionxe2x80x9d, N.Eng.J.Med., 328, p. 1686 (1993)). However, such agents, which are directed primarily to early stages of viral replication, do not prevent the production of infectious virions in chronically infected cells. Furthermore, administration of some of these agents in effective amounts has led to cell-toxicity and unwanted side effects, such as anemia and bone marrow suppression.
More recently, the focus of anti-viral drug design has been to create compounds which inhibit the formation of infectious virions by interfering with the processing of viral polyprotein precursors. Processing of these precursor proteins requires the action of virus-encoded proteases which are essential for replication (Kohl, N. E. et al. xe2x80x9cActive HIV Protease is Required for Viral Infectivityxe2x80x9d Proc. Natl. Acad. Sci. USA, 85, p. 4686 (1988)). The anti-viral potential of HIV protease inhibition has been demonstrated using peptidal inhibitors. Such peptidal compounds, however, are typically large and complex molecules that tend to exhibit poor bioavailability and are not generally consistent with oral administration. Accordingly, the need still exists for compounds that can effectively inhibit the action of viral proteases, for use as agents for preventing and treating chronic and acute viral infections.
The present invention provides a novel class of compounds, and pharmaceutically acceptable derivatives thereof, that are useful as inhibitors of aspartyl proteases, in particular, HIV aspartyl protease. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
According to a preferred embodiment, the compounds of this invention are capable of inhibiting HIV viral replication in human CD4+ T-cells. These compounds are useful as therapeutic and prophylactic agents to treat or prevent infection by HIV-1 and related viruses which may result in asymptomatic infection, AIDS-related complex (xe2x80x9cARCxe2x80x9d), acquired immunodeficiency syndrome (xe2x80x9cAIDSxe2x80x9d), or similar disease of the immune system.
It is a principal object of this invention to provide a novel class of sulfonamides which are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. This novel class of sulfonamides is represented by formula I: 
wherein:
A is selected from the group consisting of H; Het; xe2x80x94R1xe2x80x94Het; xe2x80x94R1xe2x80x94C1-C6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C4 alkoxy, Het, xe2x80x94Oxe2x80x94Het, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2)(R2) and xe2x80x94COxe2x80x94N(R2)(R2); and xe2x80x94R1xe2x80x94C2-C6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C4 alkoxy, Het, xe2x80x94Oxe2x80x94Het, xe2x80x94NR2xe2x80x94COxe2x80x94N(R2)(R2) and xe2x80x94COxe2x80x94N(R2 )(R2);
each R1 is independently selected from the group consisting of xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94C(O)xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94S(O)2, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94 and xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(O)xe2x80x94;
each Het is independently selected from the group consisting of C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C10 aryl; and 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), O, S and S(O)n, wherein said heterocycle may optionally be benzofused; and wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, xe2x80x94OR2, xe2x80x94R2, xe2x80x94N(R2)(R2), xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)(R2), xe2x80x94S(O)2xe2x80x94N(R2)(R2), xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94C(O)xe2x80x94R2, xe2x80x94S(O)nxe2x80x94R2, xe2x80x94OCF3, xe2x80x94S(O)nxe2x80x94Ar, methylenedioxy, xe2x80x94N(R2)xe2x80x94S(O)2(R2), halo, xe2x80x94CF3, xe2x80x94NO2, Ar and xe2x80x94Oxe2x80x94Ar;
each R2 is independently selected from the group consisting of H and C1-C3 alkyl optionally substituted with Ar;
B, when present, is xe2x80x94N(R2)xe2x80x94C(R3)(R3)xe2x80x94C(O)xe2x80x94;
x is 0 or 1;
each R3 is independently selected from the group consisting of H, Het, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl and C5-C6 cycloalkenyl, wherein any member of said R3, except H, may be optionally substituted with one or more substituents selected from the group consisting of xe2x80x94OR2, xe2x80x94C(O)xe2x80x94NHxe2x80x94R2, xe2x80x94S(O)nxe2x80x94N(R2)(R2), Het, xe2x80x94CN, xe2x80x94SR2, xe2x80x94CO2R2, NR2xe2x80x94C(O)xe2x80x94R2;
each n is independently 1 or 2;
D and Dxe2x80x2 are independently selected from the group consisting of Ar; C1-C4 alkyl, which may be optionally substituted with one or more groups selected from C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94R3, xe2x80x94Oxe2x80x94Ar and Ar; C2-C4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, xe2x80x94OR2, xe2x80x94R3, xe2x80x94Oxe2x80x94Ar and Ar; C3-C6 cycloalkyl, which may be optionally substituted with or fused with Ar; and C5-C6 cycloalkenyl, which may be optionally substituted with or fused with Ar;
each Ar is independently selected from the group consisting of phenyl; 3-6 membered carbocyclic ring and 5-6 membered heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n and N(R2), wherein said carbocyclic or heterocyclic ring may be saturated or unsaturated and optionally substituted with one or more groups selected from the group consisting of oxo, xe2x80x94OR2, xe2x80x94R2, xe2x80x94N(R2)(R2), xe2x80x94N(R2)xe2x80x94C(O)xe2x80x94R2, xe2x80x94R2xe2x80x94OH, xe2x80x94CN, xe2x80x94CO2R2, xe2x80x94C(O)xe2x80x94N(R2)(R2), halo and xe2x80x94CF3;
E is selected from the group consisting of Het; Oxe2x80x94Het; Hetxe2x80x94Het; xe2x80x94Oxe2x80x94R3; xe2x80x94NR2R3; C1-C6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Het; C2-C6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Het; C3-C6 saturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R4 and Het; and C5-C6 unsaturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R4 and Het; and
each R4 is independently selected from the group consisting of xe2x80x94OR2, xe2x80x94C(O)xe2x80x94NHR2, S(O)2xe2x80x94NHR2, halo, xe2x80x94NR2xe2x80x94C(O)xe2x80x94R2 and xe2x80x94CN.
It is a also an object of this invention to provide pharmaceutical compositions comprising the sulfonamides of formula I and methods for their use as inhibitors of HIV aspartyl protease.
It is a further object of this invention to provide a novel class of HIV aspartyl protease inhibitor compounds characterized by the following novel combination of structural and physicochemical features:
(1) a first and a second hydrogen bond acceptor moiety, at least one of which is more highly polarizable than a carbonyl, said moieties being the same or different, and being capable of hydrogen bonding with the hydrogen atoms of the flap water molecule of an HIV aspartyl protease when the compound is bound thereto;
(2) substantially hydrophobic moieties which associate with the P1 and P1xe2x80x2 binding pockets of said HIV aspartyl protease when the compound is bound thereto;
(3) a third hydrogen bonding moiety, which may be either a hydrogen bond donor or acceptor, capable of simultaneously hydrogen bonding to Asp25 and Asp25xe2x80x2 of said HIV aspartyl protease when the compound is bound thereto;
(4) an additional occupied volume of space of at least 100 xc3x853 when the compound is bound to the active site of said HIV aspartyl protease, said space overlapping with the volume of space that would be filled by a native substrate of said HIV aspartyl protease or a nonhyrolyzable isostere thereof;
(5) a deformation energy of binding of the compound to said HIV aspartyl protease of not greater than 10 kcal/mole; and
(6) a neutral or favorable enthalpic contribution from the sum of all electrostatic interactions between the compound and the protease when the compound is bound to said HIV aspartyl protease.
It is also an object of this invention to provide pharmaceutical compositions comprising compounds having the above-mentioned features and methods for their use as inhibitors of HIV aspartyl protease.
It is a further object of this invention to provide a method for identification, design, or prediction of HIV aspartyl protease inhibitors comprising the steps of:
(a) selecting a candidate compound of defined chemical structure containing a first and a second hydrogen bond acceptor moiety, at least one of which is more highly polarizable than a carbonyl, said moieties being the same or different; a third hydrogen bonding moiety, which may be either a hydrogen bond donor or acceptor; and at least two substantially hydrophobic moieties;
(b) determining a low-energy conformation for binding of said compound to the active site of an HIV aspartyl protease;
(c) evaluating the capability of said first and second hydrogen bond acceptor moieties to form hydrogen bonds to the flap water molecule of said HIV aspartyl protease when said compound is bound thereto in said conformation;
(d) evaluating the capability of said substantially hydrophobic moieties to associate with the P1 and P1xe2x80x2 binding pockets of said HIV aspartyl protease when said compound is bound thereto in said conformation;
(e) evaluating the capability of said third hydrogen bonding moiety to form hydrogen bonds to Asp25 and Asp25xe2x80x2 of said HIV aspartyl protease when said compound is bound thereto in said conformation;
(f) evaluating the overlap of the occupied volume of said compound when said compound is bound to said HIV aspartyl protease in said conformation and the occupied volume of a native substrate of HIV aspartyl protease or a nonhydrolyzable isostere thereof, when said polypeptide is bound to said HIV aspartyl protease;
(g) evaluating the deformation energy of binding of said compound to said HIV aspartyl protease;
(h) evaluating the enthalpic contribution of the sum of all electrostatic interactions between said compound and said HIV aspartyl protease when said compound is bound thereto in said conformation; and
(i) accepting or rejecting said candidate compound as an HIV protease inhbitor based upon the determinations and evaluations carried out in steps (b) through (h).